rs1553153329

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006015.6(ARID1A):​c.4993G>A​(p.Gly1665Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ARID1A
NM_006015.6 missense, splice_region

Scores

7
6
6
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.42
Variant links:
Genes affected
ARID1A (HGNC:11110): (AT-rich interaction domain 1A) This gene encodes a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARID1ANM_006015.6 linkuse as main transcriptc.4993G>A p.Gly1665Arg missense_variant, splice_region_variant 18/20 ENST00000324856.13 NP_006006.3
ARID1ANM_139135.4 linkuse as main transcriptc.4342G>A p.Gly1448Arg missense_variant, splice_region_variant 18/20 NP_624361.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARID1AENST00000324856.13 linkuse as main transcriptc.4993G>A p.Gly1665Arg missense_variant, splice_region_variant 18/201 NM_006015.6 ENSP00000320485 O14497-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 23, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
.;D;.;.;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;D;D
M_CAP
Benign
0.030
D
MetaRNN
Uncertain
0.72
D;D;D;D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
1.8
.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.8
.;D;D;D;.
REVEL
Uncertain
0.48
Sift
Benign
0.049
.;D;T;T;.
Sift4G
Benign
0.27
.;T;T;T;.
Polyphen
0.99, 1.0, 1.0
.;D;D;D;.
Vest4
0.81, 0.88, 0.90
MutPred
0.37
.;Gain of MoRF binding (P = 0.0185);.;.;.;
MVP
0.78
MPC
1.6
ClinPred
0.99
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.75
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.61
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.61
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553153329; hg19: chr1-27101711; API